The overall objective of this proposal is to gain a molecular understanding of the determinants of vascular permeability (VP), an early event leading to angiogenesis. Based on recent developments in the field and progress in our laboratory, we have defined a specific role of VEGF-mediated Src activity crucial for angiogenesis and VP. Mice lacking Src exhibit on VEGF-mediated VP response, yet apparently have normal angiogenesis. Thus, Src-deficient mice serve as an excellent model to evaluate the role of VP in tumor metastasis. Both in vitro and in vivo experiments will be designed to evaluate barrier function in VEGF- stimulated vessels and to measure subsequent angiogenesis and tumor metastasis. Specifically, we will 1) determine the mechanisms by which VEGF-dependent Src activity leads to VP and 2) evaluate the effects of the VEGF-mediated VP on tumor metastasis in mice deficient in individual Src family members. This work will allow identification of possible therapeutic targets to combat angiogenesis, and halt tumor progression, as well as promote angiogenesis and improve outcome following myocardial infarction.